Alzheimer's Disease (AD) is a progressive, neurodegenerative disease characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotionally stability. AD is a common cause of dementia in humans and a leading cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major public health problem throughout the world. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available and the disease is currently considered among experts to be incurable.
Dementia, for purposes of the present invention includes Alzheimer's disease (AD), vascular dementia and mixed cases. The early stages of dementia has to some degree been elucidated and defined. For example, studies have established a group of individuals that are at risk of developing dementia. These individuals suffer from mild cognitive impairment (MCI). MCI refers to a clinical state wherein the individuals are memory impaired but do not meet the clinical criteria for dementia. Petersen, et al., Practice parameter: Early detection of dementia: Mild cognitive impairment (an evidence-based review), Neurology, 56:1133-1142 (2001). The criteria used to establish MCI is as follows: 1) the presence of a subjective memory complaint, preferably corroborated by an informant; 2) preserved general intellectual functioning as estimated by performance on a vocabulary test; 3) demonstration of a memory impairment by cognitive testing; 4) intact activities of daily living; and 5) absence of dementia.
Another group of individuals that are at risk for developing dementia are those in a pre-demented state found with age associated cognitive decline (AACD) which is generally defined by a decline of more than one standard deviation in any are of cognitive functioning in comparison with age matched controls. K. Ritchie et al., Classification criteria for mild cognitive impairment: A population-based validation study, Neurology 56:3742 (2001). Ritchie et al., argues that AACD has a higher predictive validity for dementia onset. Id. at 40.
The histopathological manifestations of AD are characteristic lesions known as amyloid (or senile) plaques and neurofibrillar tangles that are found in the regions of the brain associated with memory, reasoning and cognition. Similar alterations are observed in patients with Trisomy 21 (Down's syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type.
The major constituent of amyloid plaques is amyloid β protein. Amyloid β protein is derived from the proteolytic cleavage of amyloid precursor protein (APP). Processing of APP to amyloid β protein and other APP fragments is governed by a group of enzymes known as secretases. One type of secretase, γ-secretase, is responsible for the protein cleavage that produces amyloid β protein. Compounds that inhibit either β or γ secretase activity, either directly or indirectly would reduce the production of amyloid β protein resulting in the treatment or prevention of disorders associated with amyloid β protein. Thus there is a continuing need for compounds that inhibit amyloid β protein production. The present invention meets this and related needs by providing a family of novel compounds and related methods of use.